A segment of a polypeptide chain contains three consecutive residues with the following side-chain functional groups:
• Residue X: –CH₂–OH (serine-like)
• Residue Y: –CH₂–CH₂–CH₃ (leucine-like)
• Residue Z: –CH₂–COO⁻ (glutamate-like)
The chain is folded so that these three side chains are brought into close proximity within a non-polar pocket of the protein interior.
Assume the microenvironment is largely free of bulk water but does contain a few ordered water molecules that can bridge hydrogen bonds.
Answer the questions below regarding non-covalent interactions among these side chains and the limited water molecules.
(a) Considering only pairwise interactions among side chains X, Y, and Z, list all distinct interaction pairs and rank them from weakest to strongest. Provide a brief justification for each ranking decision.
(b) Describe how the presence of one or two ordered water molecules in the pocket could alter your ranking in part (a). In your explanation, address possible formation of hydrogen-bond bridges and changes in local dielectric constant.
(c) Propose which single interaction (either direct or water-mediated) is most likely to contribute the greatest stabilization energy to this folded conformation. Justify your choice by comparing the magnitudes and directionalities of the relevant intermolecular forces.
(d) If residue Y were mutated to a phenylalanine-like side chain (–CH₂–C₆H₅), predict qualitatively how each of the interactions discussed in parts (a)–(c) would change. Support your predictions by referencing polarizability, potential π-stacking, and any new hydrogen-bonding possibilities.